Highlights from Recent Cancer Literature
Journal: Cancer Research (2015)

There is controversy about standard treatment for HER2 (ERBB2)-positive stage I breast cancer, and to date no randomized trials of adjuvant therapy have been conducted in these patients. Recurrence rates (local and distant) vary from 5% to 30% among prior studies. Tolaney and colleagues performed an uncontrolled, single-arm, multicenter study of adjuvant paclitaxel (doxorubicin and cyclophosphamide omitted) and trastuzumab (monoclonal antibody to HER2) in 406 patients and report a 3-year survival free from invasive disease rate of 98.7%. These results suggest a low rate of recurrence and serious toxicities (heart failure rate, 0.5%). Although this nonrandomized study reveals improved patient outcomes compared with historical data, it does not necessarily establish trastuzumab-based chemotherapy as standard of care for all patients with small HER2-positive tumors.Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015;372:134–41.Comparing the number and replicative capacity of stem cells with the lifetime risk of cancer across 31 distinct tissue types, Tomasetti and Vogelstein obtained a statistically significant correlation. This association suggested that only one third of the cancer risk in these tissues was due to inherited predisposition or environmental factors. The bulk of these cancers arose from random mutations during DNA replication of stem cells regulating homeostasis for each tissue. To distinguish this stochastic component from risk due to environmental or inherited mutations, they developed an “extra risk score” (ERS). Tumors with high ERS numbers (D-tumors) had known links to environmental or hereditary risk factors. In tumors with low ERS numbers (R-tumors), stochastic factors dictated risk of occurrence. These results have important public health implications, as they suggest that D-tumors are significantly more preventable than R-tumors.Tomasetti C, Vogelstein B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78–81.Using tail vein injection and orthotopic tumor transplant models, Yumimoto and colleagues conditionally ablated the Fbxw7 E3-ligase in bone marrow–derived cells (BMDC), observing lung metastases and increased numbers of Ly6C- and F4/80 (EMR1)-positive cells in tumor surrounding regions. As these differences were not present in marrow, ablation of Fbxw7 in BMDCs altered cell migration or recruitment to metastatic sites. Ablation of Fbxw7 in marrow increased serum CCL2 levels, and knockdown/inhibition of CCR2 in bone marrow–derived stromal cells (BMSC) reduced burden of lung tumors. Accumulation of the NOTCH1 intracellular domain, an FBW7 substrate, drove CCL2 expression and metastatic tumor burden. Expression levels of FBXW7 and CCL2 were negatively correlated, whereas low levels of serum FBXW7 were associated with shortened disease-free survival in triple-negative disease. Thus, FBXW7 may act non–cell autonomously to recruit BMSCs to metastatic foci and promote tumor growth.Yumimoto K, Akiyoshi S, Ueo H, Sagara Y, Onoyama I, Ueo H, et al. F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. J Clin Invest 2015 Jan 2. [Epub ahead of print].Disseminated tumor cells (DTC) can evade antiproliferative therapies because they persist as slow-cycling/dormant solitary tumor cells in the bone marrow microenvironment. Nakamura and colleagues verified that head and neck squamous cell carcinoma (HNSCC) DTCs from bone marrow upregulated TGFβ2. However, they now show that, via induction of SDF1 (CSCL12)-CXCR4 signaling, these DTCs coordinated a slow-cycling phenotype that drove intrinsic resistance to cisplatin. The phenotype was tightly linked to TGFβ2 expression and not TGFβ1 or TGFβ3, which oppose TGFβ2 in this model. These studies identify SDF1 and CXCR4 downstream of TGFβ2 signaling as linked to HNSCC DTC dormancy in the bone marrow. These pathways represent potential targets to block drug resistance in systemically occurring dormant DTCs. Caution must be taken, however, as reactivating dormant cells may accelerate progression in multiple organs and lead to additional drug resistance mechanisms.Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, et al. Intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells. Oncotarget 2014 Nov 25. [Epub ahead of print].Most melanomas carry somatic mutations in BRAF, with another 20% having mutations in NRAS. Vemurafenib inhibits mutant BRAF, with impressive responses in BRAF-mutant melanoma. However, most patients develop resistance, predominantly due to paradoxical induction of MEK signaling in a CRAF (RAF1)-dependent manner. Girotti and colleagues describe two novel pan-RAF inhibitors that break the paradox by inhibiting, rather than activating, MEK in NRAS-mutant cells. These compounds were also potent inhibitors of SRC family kinases (SFK), upstream regulators of MEK/ERK. The authors found dramatically elevated active ERK and SRC in vemurafenib-resistant patient-derived xenografts. Importantly, resistant tumors retained sensitivity to the two novel pan-RAF inhibitors. The ability of these drugs to equipotently target mutant BRAF, CRAF, and SFKs promises enhanced efficacy and suggests therapeutic potential in upcoming clinical trials.Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, et al. Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell 2015;27:85–96.RAGE (AGER) is a multifunctional receptor associated with inflammation and cancer. Nasser and colleagues show that RAGE is upregulated in triple-negative breast cancer cells, in both primary tumors and lymph node metastases. RAGE-deficient mice show a reduced propensity for breast tumor growth. Systemic administration of RAGE neutralizing antibody inhibited development of lung metastases. The authors demonstrate that RAGE binds to the proinflammatory ligand S100A7, which activates ERK and NF-κB, promoting cell migration. Administration of either RAGE neutralizing antibody or soluble RAGE in S100A7 transgenic mice inhibited tumor progression and metastasis. RAGE/S100A7 modulated the tumor microenvironment by recruiting MMP9-positive tumor-associated macrophages. These findings suggest that RAGE/S100A7 signaling links inflammation to aggressive breast cancer and support RAGE as a candidate biomarker for triple-negative breast cancers.Nasser MW, Nissar WB, Ahirwar DK, Powell CP, Ravi J, Elbaz MM, et al. RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment. Cancer Res; Published OnlineFirst January 8, 2015; doi:10.1158/0008-5472.CAN-14-2161.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.